Obesity is a well-known risk factor for the development of many common diseases such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). Obesity is best viewed as any degree of excess adiposity that imparts a health risk. When energy intake exceeds expenditure, the excess calories are stored predominately in adipose tissue, and if this net positive balance is prolonged, obesity results, i.e. there are two components to weight balance, and an abnormality on either side (intake or expenditure) can lead to obesity. This process may be counteracted by increasing the energy expenditure or decreasing the energy intake. There is, therefore, a need for pharmaceutical agents that are capable of controlling excess adipose tissue for instance by increasing the energy expenditure or decreasing the energy intake.
The body gets energy through the oxidation of food such as glucose and fatty acids. It is known that mitochondria control metabolism in individual cells by burning sugars and fats. One of its primary functions is oxidative phosphorylation, a process through which energy derived from metabolism of fuels like glucose or fatty acids is converted to ATP. The generation of ATP in the mitochondria is coupled to the oxidation of NADH which results in the transportation of protons in the electron transport chain. Chemical uncouplers can inhibit efficient energy (ATP) production in cells with mitochondria. They uncouple oxidative phosphorylation by carrying protons across the mitochondrial membrane, leading to a rapid consumption of energy (the energy expenditure) without generation of ATP. In other words, the uncouplers flood the mitochondrial matrix with protons, and the oxidation of NADH continues but instead of generating energy in the form of ATP, the energy of the proton gradient is lost as heat.
The manipulation of chemical uncouplers of mitochondria in order to decrease fat deposits has been a scientific goal for more than eighty years. See Simkins S “Dinitrophenol and desiccated thyroid in the treatment of obesity: a comprehensive clinical and laboratory study”. J Am Med Assoc 108: 2110-2117 (1937) and Fleury C et al, Nature Genetics 15, 269-272 (1997), Uncoupling Protein-2: A Novel Gene Linked to Obesity and Hyperinsulinemia. The best known chemical uncoupler is 2,4-dinitrophenol (DNP), which has been shown to increase energy expenditure in humans as well as animals. However, chemical uncouplers are often toxic. Concerns about dangerous side-effects led to the removal of DNP from the market.
There is a need for safe mitochondrial uncouplers that can safely produce the desired medical effect without harming the individual. The novel phenyl derivatives disclosed herein satisfy these needs.